Project Summary: Dementia has a high global prevalence due to the aging population, places an enormous burden on health care systems. Alzheimer's disease (AD) is the most common cause of dementia, and it is widely believed that the accumulation of Amyloid beta (A?) peptide is a key event in the pathogenesis of AD, representing preclinical disease stages. Cerebral iron is strongly implicated as a cofactor in the pathogenesis of AD, and its overload accelerates A? production and promotes the toxicity of the A? peptide. However, the impact of brain iron load, and its combined effect with regional A?-plaque-load on cognitive performance in AD and its precursor, mild cognitive impairment (MCI), is lacking. Our overall aim is to study the role of brain iron load and its possible synergistic effect with A?- plaque-load in the development of cognitive decline, MCI and dementia, in particular AD. We are uniquely positioned to carry out this project in the Atherosclerosis Risk in Communities (ARIC) study, which has collected clinical data from cohort participants over the past 30 years. A biracial sample of elderly adults was evaluated by brain MRI, brain florbetapir positron emission tomography (PET), and cognitive tests at study visit 5 with repeat testing underway at visit 6. We will utilize the phase signal from gradient echo MRI data at visit 6 (n=1,000) to compute quantitative susceptibility mapping (QSM). Brain iron load will be automatically quantified using our recent developed susceptibility multi-atlas tool. Accordingly, we propose to determine the contribution of cerebral iron load based on QSM measures in ARIC participants with the following specific aims. Aim 1: To determine if increased cerebral iron measures are independently associated with cognitive performance in dementia or MCI in ARIC participants aged 73-94 years. Aim2: To estimate the combined effects of A?-plaque-load as measured by florbetapir PET and increased cerebral iron-load on the progression of cognitive outcomes. Aim 3: To relate known midlife vascular risk factors and blood ferritin levels with cerebral iron load measured in late-life.